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BACKGROUND: Nitric oxide is a key signalling molecule in the pathogenesis of inflammation, but its role in acute pancreatitis and related abdominal pain induced by secretory phospholipase A2 (sPLA2 ) from Crotalus durissus terrificus (Cdt) venom has not been investigated. METHODS: Male Wistar rats were i.v. injected with L-NAME (20 mg/kg), aminoguanidine (AG, 50 mg/kg), 7-nitroindazole (7-NI, 10 mg/kg) or vehicle 10 min before or 60 min after the injection of sPLA2 (300 µg/kg) into the common bile duct. After 4 h of sPLA2 injection, abdominal hyperalgesia and inflammation were assessed in addition to serum amylase, nitrite/nitrate (NOx), pancreas lipoperoxidation and 3-nitrotyrosine (3-NT) contents. RESULTS: sPLA2 -induced acute pancreatitis, related abdominal hyperalgesia, hyperamylasemia and increased concentration of NOx were not correlated with lipoperoxidation or increased 3-NT in the pancreas. Pretreatment with all the nitric oxide synthase (NOS) inhibitors significantly reduced abdominal mechanical hyperalgesia, but only iNOS blockade by AG suppressed pancreas oedema and serum NOx increase. The therapeutic approach with all the NOS inhibitors produced a similar reduction pattern of the abdominal hyperalgesia, but AG treatment also inhibited serum hyperamylasemia and NOx concentrations and pancreatic myeloperoxidase. The nNOS blockade by 7-NI treatment also inhibited myeloperoxidase activity in both pancreas and lung. CONCLUSIONS: Therapeutic blockade of iNOS or nNOS provides benefits in terms of inhibition of the acute pancreatitis-related abdominal hyperalgesia, while iNOS inhibition also ameliorates the inflammatory cell influx to the pancreas and reduces the resultant hyperamylasemia and NOx levels, thus representing alternative pharmacological strategies for treatment of clinical pancreatitis associated with increased PLA2 .

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Two thirds of breast cancers express estrogen receptors (ER). ER alpha (ERα) mediates breast cancer cell proliferation, and expression of ERα is the standard choice to indicate adjuvant endocrine therapy. ERbeta (ERß) inhibits growth in vitro; its effects in vivo have been incompletely investigated and its role in breast cancer and potential as alternative target in endocrine therapy needs further study. In this work, mammary epithelial (EpH4 and HC11) and breast cancer (MC4-L2) cells with endogenous ERα and ERß expression and T47-D human breast cancer cells with recombinant ERß (T47-DERß) were used to explore effects exerted in vitro and in vivo by the ERß agonists 2,3-bis (4-hydroxy-phenyl)-propionitrile (DPN) and 7-bromo-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol (WAY). In vivo, ERß agonists induced mammary gland hyperplasia and MC4-L2 tumour growth to a similar extent as the ERα agonist 4,4',4''-(4-propyl-(1H)-pyrazole-1,3,5-triyl) trisphenol (PPT) or 17ß-estradiol (E2) and correlated with higher number of mitotic and lower number of apoptotic features. In vitro, in MC4-L2, EpH4 or HC11 cells incubated under basal conditions, ERß agonists induced apoptosis measured as upregulation of p53 and apoptosis-inducible factor protein levels and increased caspase 3 activity, whereas PPT and E2 stimulated proliferation. However, when extracellular signal-regulated kinase 1 and 2 (ERK ½) were activated by co-incubation with basement membrane extract or epidermal growth factor, induction of apoptosis by ERß agonists was repressed and DPN induced proliferation in a similar way as E2 or PPT. In a context of active ERK ½, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/RAC-alpha serine/threonine-protein kinase (AKT) signalling was necessary to allow proliferation stimulated by ER agonists. Inhibition of MEK ½ with UO126 completely restored ERß growth-inhibitory effects, whereas inhibition of PI3K by LY294002 inhibited ERß-induced proliferation. These results show that the cellular context modulates ERß growth-inhibitory effects and should be taken into consideration upon assessment of ERß as target for endocrine treatment.

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Despite the benefits of using surgical meshes to repair abdominal and inguinal hernias, there are increasing reports of mesh migration into the gastrointestinal and urinary tracts-a complication that cannot be overlooked or neglected. Resolution of such cases can be difficult and depends on the degree of migration and the anatomical site involved. The present paper reports the case of a 68-year-old patient undergoing a trans-ureteral resection of a possible bladder malignancy diagnosed following clinical and radiological evaluation. During the procedure (cytoscopy), it was found that migration of a mesh was mimicking the urological disease initially suspected. A polypropylene mesh had been inserted into the right inguinal region 20 years previously to repair an inguinal hernia. This is one of only a few case reports on mesh migration presenting as a suspected bladder malignancy.

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We show that ethyl 2-oxo-2H-chromene-3-carboxylate (EOCC), a synthetic coumarin, irreversibly inhibits phospholipase A(2) (sPLA2) from Crotalus durissus ruruima venom (sPLA2r) with an IC(50) of 3.1 +/- 0.06 nmol. EOCC strongly decreased the V(max) and K(m), and it virtually abolished the enzyme activity of sPLA2r as well as sPLA2s from other sources. The edema induced by sPLA2r + EOCC was less than that induced by sPLA2r treated with p-bromophenacyl bromide, which was more efficient at neutralizing the platelet aggregation activity of native sPLA2r. Native sPLA2r induced platelet aggregation of 91.54 +/- 9.3%, and sPLA2r + EOCC induced a platelet aggregation of 18.56 +/- 6.5%. EOCC treatment also decreased the myotoxic effect of sPLA2r. Mass spectrometry showed that EOCC formed a stable complex with sPLA2r, which increased the mass of native sPLA2r from 14,299.34 Da to 14,736.22 Da. Moreover, the formation of this complex appeared to be involved in the loss of sPLA2r activity. Our results strongly suggest that EOCC can be used as a pharmacological agent against the sPLA2 in Crotalus durissus sp. venom as well as other sPLA2s.

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The present study aimed to correlate the DNA replication timing of different genes with genetic damage and frequency of cancer. Using a fluorescence in situ hybridisation (FISH) approach, the replication timing of three loci, two human genes possessing transcriptional capability and involved in both the cellular response to genetic damage and cancer development (TP53 and RB1) and the non-coding locus D22S163, was evaluated. The data obtained show that normal human lymphocytes exposed in vitro to known DNA-damaging agents, e.g. H2O2, ionizing radiation and mitomycin C, exhibit an asynchronous replication of the genes TP53 and RB1. In vivo studies were performed in three different populations from Kazakhstan. In two of these populations that are living in polluted areas and have higher cancer mortalities than people living in a control area, a DNA replication behaviour similar to that observed in human lymphocytes exposed in vitro to known genotoxic agents was detected. The results obtained further indicate that DNA damage hampers replication and FISH represents a fast and accurate method of assessing asynchronous replication by providing an important tool to evaluate DNA damage at a populational level.

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Stress echocardiography is widely used in the investigation of coronary heart disease. Exercise stress echocardiography offers the advantage of visualizing myocardial motion abnormalities during physiological stress testing. The authors report the use of atropine, as an adjunct to exercise echocardiography, in risk stratification after myocardial infarction.

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OBJECTIVE: To image the thoracic aorta by transesophageal echocardiography (TEE) and study atherosis (morphology and extent of atheroma plaques) and sclerosis (stiffness) and secondarily correlate them with serum lipid levels (cholesterol, HDL, LDL and triglycerides). METHODS: We studied 29 patients (pts) who underwent TEE electively (male 18 pts, age 57.8 +/- 14.6 years). The parameters evaluated were: the stiffness coefficient = ln (PAsist/PAdiast)/(Dsyst/Dmin), and the morphology, location and extent of atheroma plaques. The systolic distension (Dsyst) was the difference between the maximal and the minimal dimensions (Dmin) of the aortic diameter measured by M mode. The lesions were classified in 4 degrees (0-3): 0--normal intima, 1--intimal thickening, 2--atheroma, 3--complicated lesion. Five aortic segments were studied: arch, D1-D4 (descending aorta at 5 cm intervals from the first 25 cm distal of the incisors line). We calculated the individual score = 1 x theta 1/180 + 2 x theta 2/180 + 3 x theta 3/180, theta n represents the angles occupied by the lesions and n (1-3) the severity of atherosis of each lesion. The total atherosis index (TAI) was sigma scores/(n. degree of visualized segments). RESULTS: The arch was not visualized in 3 pts, and the segment D4 was only visualized in 3 pts. TAI mean = 0.82 +/- 0.74, stiffness coefficient mean (SC) = 9.56 +/- 15.072. There were no significant correlations between the lipid levels and the TAI or SC. The only significant positive correlations were: TAI vs age (r = 0.62, p < 0.001) and SC and diastolic blood pressure (BP) (r = 0.42, p < 0.05). CONCLUSIONS: The best visualized segments belong to the descending aorta (25 to 40 cm from the incisors). In this group of patients the lipid levels did not seem to be a preponderant factor in aortic atherosclerosis. The most important factors were age for atherosis and BP for sclerosis.

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The authors report a case study of a 60 year-old-male admitted to the Coronary Care Unit with severe chest pain, hypertension and ST depression on the anterior and lateral leads of the electrocardiogram. A diastolic murmur was heard in the aortic area. The chest X-ray showed an enlarged superior mediastinum. The transthoracic echocardiogram revealed an image that indicated an intimal flap above the aortic plane with severe aortic regurgitation. An aortography was performed and confirmed the diagnosis of acute type A aortic dissection with partial obstruction of the left main coronary artery, probably due to compression by the hematoma. The patient underwent emergency surgical repair with replacement of the aortic valve and ascending aorta. The patient survived without complications post surgery and was discharged ten days after onset of symptoms. Twenty months later, the patient was asymptomatic and the transesophageal echocardiogram showed a dissection of the descending thoracic aorta, mild aortic regurgitation and good left ventricular systolic function.

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The authors report a case study of a 60 year-old-male admitted to the Coronary Care Unit with severe chest pain, hypertension and ST depression on the anterior and lateral leads of the electrocardiogram. A diastolic murmur was heard in the aortic area. The chest X-ray showed an enlarged superior mediastinum. The transthoracic echocardiogram revealed an image that indicated an intimal flap above the aortic plane with severe aortic regurgitation. An aortography was performed and confirmed the diagnosis of acute type A aortic dissection with partial obstruction of the left main coronary artery, probably due to compression by the haematoma. The patient underwent emergency surgical repair with replacement of the aortic valve and ascending aorta. The patient survived without complications post surgery and was discharged ten days after onset of symptoms. Twenty months later, the patient was asymptomatic and the transesophageal echocardiogram showed a dissection of the descending thoracic aorta, mild aortic regurgitation and good left ventricular systolic function.

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The diagnosis of coronary artery disease in women has been thought to be more difficult than in men, owing to the lower overall prevalence of disease in women, as well as more subtle clinical presentations and unspecific changes in ST segment. The authors report a clinical case of a 61-year old woman, with low cardiovascular risk and history of atypical chest pain and a positive treadmill exercise test on the inferior leads. She did an exercise echocardiogram that revealed severe hypokinesis on the anterior wall and septum with late normalization. The patient was submitted to a coronary angiography that revealed normal arteries. An echocardiogram with hyperventilation was later performed and showed the same ischemic changes as exercise did, on the inferior leads but no regional wall motions abnormalities occurred. The patient is currently asymptomatic under calcium antagonist treatment.

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Stress echocardiography is widely used in the evaluation of coronary artery disease. Dobutamine stress echocardiography has been the preferred method, but many centers have adopted exercise stress echocardiography, which can visualize myocardial motion during physiologic stress testing. The complications of this method in the post-myocardial infarction period are the same as those identified in conventional exercise testing. We report a case of myocardial rupture in the postinfarction period during exercise stress echocardiography.

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The authors review the methodology and clinical applications of exercise echocardiography. This is a method that can be done in most of the patients with indication to the treadmill exercise test. There is an excellent relationship between costs and benefits associated to high sensitivities and specificities in the diagnosis of ischemia. This can lead to the preferential use of this technique, in the opinion of the authors, when it is indicated and in all patients that can do exercise.

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UNLABELLED: Previous studies on chronotropic incompetence (CI) in patients with congestive heart failure (CHF) have defined it as the inability to achieve > 80% of age predicted maximum heart rate (HR) (adequacy of HR response to submaximal exercise levels not being considered). The metabolic chronotropic relation (MCR) concept proposed by Wilkoff allows the assessment of the entire chronotropic function. The value of such an approach for the evaluation of CI in patients with CHF, and its relation to exercise capacity, is unclear at present. METHODS: We imposed maximal symptom-limited treadmill exercise testing while measuring breath-by-breath oxygen consumption, using CAEP protocol, in 25 patients (19 men), 49 +/- 10 years, all in sinus rhythm, with CHF secondary to dilated cardiomyopathy (17) or ischemic heart disease (8), NYHA class II-III. Anaerobic threshold (AT) was attained by all. No exercise was terminated due to arrhythmia or ischemia. MCR was calculated as the slope of the relation between the percentages of HR and metabolic reserves achieved at the end of each exercise stage. Using 2.0 standard deviations below the mean level of MCR in healthy controls, we defined an MCR value < 0.84 as abnormal. The parameters analysed were: age, drug therapy, fractional shortening (FS-%), resting HR (RHR-bpm), exercise duration (DUR-min), peak HR (HRp), peak oxygen consumption (VO2p-ml/kg/min), percentages of predicted maximal HR (% PMHR) and VO2 (% PMVO2), peak ventilatory equivalent for CO2 (VE/VCO2-L/min), time to AT (T-AT), and VO2 at AT (VO2-AT). RESULTS: MCR was normal (1.01 +/- 0.18-0.86 to 1.19) in 10 patients--Group I, and abnormal (0.66 +/- 0.13-0.42 to 0.81) in 15 (60%) patients--Group II. A similar proportion of patients in both groups were taking ACE inhibitors, digoxin and amiodarone. [table: see text] CI defined as an inability to achieve a % PMHR > 80% occurred only in 6 (24%) patients, all in Group 2 (p = 0.022 versus abnormal MCR). CONCLUSIONS: In CHF patients, CI assessed as an abnormal MCR is frequent, and relates to an impaired exercise capacity.

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UNLABELLED: Maximal oxygen consumption (VO2max) has an important prognostic value in patients with congestive heart failure (CHF). However, it requires a maximal exercise test, not often available for these patients. To overcome this limitation, we examined whether a simple time integral of oxygen pulse (OP) to submaximal exercise levels correlates with VO2max. METHODS: We performed a maximal symptom-limited treadmill exercise test, while measuring breath-by-breath oxygen consumption, using the CAEP protocol, in 24 patients with CHF (51 +/- 11 years, 18 males, sinus rhythm). No exercise was terminated due to ischemia or arrhythmias. All patients attained anaerobic threshold. Besides standard parameters, OP (ml) and time integral of OP (OPTI) were calculated at 2 minutes (OP-2 min and OPTI-2 min) and at 4 minutes (OP-4 min and OPTI-4 min) of exercise. Patients were divided in two groups according to VO2max: group I--VO2max > or = 16 ml/kg/min (14 patients) and group II--VO2max < 16 (10 patients). RESULTS: Age, sex, body surface and CHF etiology were similar in both groups. Exercise duration, maximal OP, time to anaerobic there shold, VO2 and OP at anaerobic there shold were higher in group I (p < 0.05). Comparing group I vs group II--OP-2 min: 6.2 +/- 1.5 vs 5.0 +/- 1.2 ml (p = 0.026); OP-4 min: 7.6 +/- 1.9 vs 5.4 +/- 1.2 (p = 0.001); OPTI-2 min: 3.1 +/- 1.1 vs 2.2 +/- 0.9 (p = 0.021) and OPTI-4 min: 15.2 +/- 4.4 vs 9.3 +/- 3.1 (p = 0.0007). The best correlation with VO2max was obtained for OPTI-4 min (r = 0.696). An OPTI-4 min value > or = 10 occurred in 13 patients of group I and in two patients of group II (p = 0.00013), with a predictive value of 87% for VO2max > 16 (sensitivity = 93%, specificity = 80%)--kappa index = 0.739. CONCLUSIONS: OPTI-4 min can be a useful tool for assessing cardiocirculatory functional status in patients with CHF and unable to perform a maximal exercise test.

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Transthoracic echocardiography has important limitations in the diagnosis of sinus venosus atrial septal defects in adults because of the posterior location of the defect. We review the role of transesophageal echocardiography in the diagnosis of this congenital heart disease in nine patients, as well as in the identification of associated abnormal pulmonary venous connections.

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OBJECTIVE: To analyse the recovery of oxygen consumption (VO2), ventilation (VE) and carbon dioxide production (VCO2) after maximal cardiopulmonary exercise testing, and to assess the possibility of recovery parameters becoming new markers of functional impairment. METHODS: Thirty-eight patients (30 males, mean age 56 +/- 11 years) with dilated cardiomyopathy performed maximal, symptom limited, treadmill exercise test with breath-by-breath respiratory gas analysis. The patients were divided in two groups, according to maximal oxygen consumption above or below 14 ml/kg/min (group I and group II, respectively). During the recovery, we analyzed the time to reach 50% of the maximal values of VO2 (T1/2 r VO2), VE (T1/2 e VE) and VCO2 (T1/2 r VCO2) in each group. RESULTS: Twenty-seven patients had a VO2max above 14 ml/kg/min (group I) and 11 had a VO2max below 14 ml/kg/min (group II). The results were as follows: T1/2 r VO2max 109 +/- 21 sec in group I versus 177 +/- 79 sec in group II (p = 0.0001). T1/2 r VCO2max 124 +/- 28 sec in group I versus 201 +/- 88 sec in group II (p = 0.0001) and T1/2 rVEmax 146 +/- 47 sec in group I versus 229 +/- 47 sec in group II (p = 0.0002). CONCLUSIONS: Patients with a poor functional capacity show a delay in the half recovery times of oxygen consumption, ventilation and carbon dioxide production. These data suggest that these parameters may be used as new markers of the level of functional impairment.

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OBJECTIVE: To evaluate whether the changes in the ventilatory equivalent for carbon dioxide (VE/VCO2), during the early stages of cardiopulmonary exercise testing, can predict maximal oxygen consumption (VO2max) in patients with chronic heart failure. METHODS: We studied 38 patients (30 males, mean age 56 +/- 11 years) with chronic heart failure. All patients performed maximal symptom limited, treadmill exercise test with breath-by-breath respiratory gas analysis. They were divided in two groups according to their maximal oxygen consumption (group I-VO2max above 14 ml/kg/min and group II-VO2max below 14 ml/kg/min). In both groups, we analysed VE/VCO2 at rest, at the anaerobic threshold (AT) and at peak exercise, and the percentage of VE/VCO2 reduction from rest to AT. RESULTS: Eleven patients had a VO2max below 14 ml/kg/min (group II). At rest VE/VCO2 = 53 +/- 13 in group II versus 47 +/- 10 in group I (p = 0.048), at the AT VE/VCO2 = 46 +/- 12 in group II versus 36 +/- 7 in group I (p = 0.001) and at peak exercise VE/VCO2 = 46.2 +/- 13 in group II versus 36.2 +/- 6 in group I (p = 0.0002). There was a 24% reduction in the VE/VCO2, from rest to AT in group I, compared to a 16% reduction in group II (p = 0.004). A reduction in the VE/VCO2 from rest to AT less than 16% predicted a VO2max below 14 ml/kg/min with a sensitivity of 60% and a specificity of 93%. CONCLUSIONS: Patients with severe functional impairment have higher values of VE/VCO2 in all exercise stages. A reduction of VE/VCO2 from rest to anaerobic threshold of less than 16% is a high specific predictor of a VO2max below 14 ml/kg/min.

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Right ventricle dysplasia (RVD) is a rare clinical entity, described in young people, and a known cause of ventricular arrhythmias and sudden death. A genetic transmission has been suggested from the study of familial cases. The disease is characterized by a dilated right ventricle, cardiac infiltration with fatty tissue and focal fibrosis. Lymphoplasmocyte infiltrates are documented. The diagnosis is based on electrocardiography, echocardiography, magnetic resonance imaging and right ventricular endomyocardial biopsy. The authors report a case of a young woman with symptomatic ventricular tachycardia (VT) in whom the diagnosis of RVD was established. Programmed ventricular stimulation was used to reproduce the clinical VT and to test the efficacy of the anti-arrhythmic drug therapy. The diagnosis criteria and therapeutic options are discussed.

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